The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha.

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFalpha protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFalpha) and aha-1 (HIFbeta), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2alpha-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2alpha, but not HIF-1alpha. These results identify TWIST1 as a direct target gene of HIF-2alpha, which may provide insight into the acquired metastatic capacity of hypoxic tumors.

Hypoxia-inducible factor 1 alpha is essential for hypoxic p27 induction in endometrioid endometrial carcinoma.

Hypoxia-inducible factor 1alpha (HIF-1alpha) plays an essential role in the adaptive response of cells to hypoxia. The cyclin-dependent kinase inhibitor p27(Kip1) is highly expressed in the normal endometrium but is lost during endometrial carcinogenesis. However, in high-grade cancers, p27 re-expression is observed. We analysed the role of HIF-1alpha in hypoxia-induced expression of p27 in vitro and in vivo in endometrial cancer. Paraffin-embedded specimens from endometrioid endometrial carcinoma (n = 39) were stained immunohistochemically for HIF-1alpha, p27, and Ki67. HEC1B, an endometrial carcinoma cell line, was cultured under normoxic or hypoxic conditions in the presence or absence of transiently expressed short hairpin RNAs targeting HIF-1alpha. Protein expression of p27 and HIF-1alpha was assessed by western blotting. Immunohistochemical staining revealed perinecrotic HIF-1alpha expression in 67% of the cases and p27 staining centrally in the tumour islands, mostly around necrosis, in 46% of the cases. In 50% of the tumours with perinecrotic HIF-1alpha expression, p27 and HIF-1alpha perinecrotic/central co-localization was observed. In these tumour sections, hypoxia-associated p27 expression showed less proliferation around necrosis. Analysis of cultured endometrial carcinoma cells demonstrated that p27 protein expression is induced by hypoxia. This induction was abrogated by transient knockdown of HIF-1alpha using RNAi. Furthermore, hypoxia induced cell cycle arrest in HEC1B cells. We conclude that, in endometrioid endometrial carcinoma, p27 re-expression by hypoxia is HIF-1alpha-dependent and leads to cell cycle arrest. This may contribute to the survival of cancer cells in hypoxic parts of the tumour.

Hypoxia-inducible factor-1alpha expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas.

Hypoxia-inducible factor-1 alpha (HIF-1alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1 and the key factor in cellular response to low oxygen tension. Expression of HIF-1alpha protein is associated with poor patient survival and therapy resistance in many types of solid tumors. Insight into HIF-1alpha regulation in solid tumors is important for therapeutic strategies. In this study, we determined the pathophysiological relevance of HIF-1alpha regulation by the oncogenic phosphatidylinositol 3'-kinase (PI 3-kinase)/Akt signaling pathway. We modeled the physiology of hypoxic tumor regions by culturing carcinoma cells under low oxygen tension in the absence of serum. We observed that hypoxic induction of HIF-1alpha protein was decreased by serum deprivation. Overexpression of dominant-active Akt1 restored HIF-1alpha expression, whereas inhibition of PI 3-kinase activity reduced hypoxic HIF-1alpha protein levels to a similar extent as serum deprivation. Immunohistochemical analysis of 95 human breast cancers revealed that lack of Akt1 phosphorylation correlates with low HIF-1alpha levels. To our knowledge, this is the first reported comparison between HIF-1alpha expression and Akt phosphorylation in human carcinomas. We conclude that Akt activity is physiologically relevant for HIF-1alpha expression in breast cancer. This implies that HIF-1alpha function might be therapeutically targeted by inhibition of the PI 3-kinase/Akt pathway.

Trends in hormonal management of prostate cancer: a population-based study in Ontario.

OBJECTIVE: To provide a population-based description of current practice in the use of hormonal management of prostate cancer. DESIGN,SETTING & PARTICIPANTS: All men in Ontario, Canada, age 65 and older, with confirmed prostate cancer starting maintained hormonal therapy, from July 1992 through December 1998 (11,435 patients). Data sources included the provincial drug benefit plan, hospital services data, and Ontario Cancer Registry. OUTCOME MEASURES: Rates and trends in the use of: surgical or medical castration; total androgen blockade (TAB); and monotherapies based on steroidal or nonsteroidal antiandrogens. RESULTS: In 5.5 years, use of 'standard' therapy based on surgical or medical castration alone dropped from 36% to 26% of patients, while the use of TAB doubled from 22% to 41%. Approximately 15% of patients received nonsteroidal antiandrogens without evidence of therapy aimed at central androgen blockade. Marked regional differences were observed and not explained by patient age or practitioner specialty. CONCLUSIONS: New hormonal therapies for prostate cancer have implications in terms of disease control, patient survival, side effects, and costs. Rapid growth in prescribing of antiandrogens may represent an unnecessary expense for public or private payers, and observed regional differences likely reflect lack of consensus on the relative merit of TAB. Patients and practitioners must have current information on the advantages and disadvantages of different therapeutic options, and quality-of life, particularly with respect to emerging drug therapies.

Randomized trial of a patient decision aid for choice of surgical treatment for breast cancer.

A decision aid for the surgical treatment of early breast cancer was evaluated in a randomized controlled trial. The decision aid, a tape and workbook, includes explicit presentation of probabilities, photographs and graphics, and a values clarification exercise. Community surgeons were randomized to use the decision aid or a control pamphlet. Patients completed a questionnaire prior to using the decision aid, after reviewing it but prior to surgery, and 6 months after enrollment. There was no difference in anxiety, knowledge, or decisional regret across the 2 groups. There was a nonsignificant trend toward lower decisional conflict in the decision aid group. A subgroup of women who were initially leaning toward mastectomy or were unsure had lower decisional conflict. Although the decision aid had minimal impact on the main study outcomes, a subgroup may have benefited. Such subgroups should be identified, and appropriate decision support interventions should be developed and evaluated.

Clinical factors affecting physicians' management decisions in cases of female partner abuse.

BACKGROUND AND OBJECTIVES: This study determined which clinical factors influence Canadian primary care physicians' management decisions in cases of female partner abuse. METHODS: We used a cross-sectional survey design and randomly sampled (n = 2,014) English-speaking Canadian physicians with a primary interest in family or general practice who were practicing in any of the 12 provinces and territories in Canada and who were active in private practice and registered to prescribe. Respondents completed a questionnaire that required them to score management decision plans in response to case scenarios illustrating typical office-based situations that might involve domestic violence. RESULTS: The response rate was 50.7% (n = 1,022). Using forward stepwise regression analysis, the strongest predictor of whether a physician endorsed a management plan in response to violence was whether the woman acknowledged or revealed the abuse. Male physicians were more likely than females to endorse talking with the suspected abuser if he was known to them, regardless of the quality of this patient-physician relationship with the abuser. CONCLUSIONS: Decisions about whether to deal with the abuse or the selection of a management plan are not dependent on the severity of the physical abuse and the emotional consequences. Whether a woman acknowledges or reveals the abuse, as well as whether both the male and female patients are in the physician's practice, are predictive of whether a physician's response to a case scenario involves dealing with spousal abuse and how he/she will address it.

Ontario hospitals' purchasing practices for hip and knee prostheses: a survey.

OBJECTIVES: To determine the makes, models and prices of the implants provided by Ontario hospitals for hip and knee replacements and the policies and procedures governing purchases. DESIGN: A questionnaire survey of hospitals with telephone follow-up. STUDY POPULATION: Seventy-nine public hospitals in Ontario in which 10 or more hip or knee replacements were carried out in the fiscal year 1993/94. SURVEY RESPONSE: Seventy-six hospitals returned questionnaires (96% response rate), reporting on 4950 primary hip and 5107 primary knee implants. Sixty-two hospitals reported volumes and prices for 19 models used in 2961 hip implants. Information on price but not makes and models was available for 1989 hip implants. Model and price information was missing for 340 hip prostheses. Fifty-seven hospitals identified the models and prices for 3460 knee implants. Twenty-five hospitals provided prices but not specific models names for 1647 knee implants and hybrids. OUTCOME MEASURE: The prices paid for prostheses. RESULTS: The average price of hip implants was Can$2141 (range from Can$650 to Can$3559). The average price for knee implants was Can$2412 (range from Can$1178 to Can$3777). The averages and ranges were about the same for specified and unspecified models and hybrids. The variations were unrelated to hospital policies about the numbers of procedures to be provided or the procedures for making purchases from suppliers. CONCLUSIONS: Savings of Can$13.7 million could have been made in Ontario during the fiscal year 1993/94 had the lowest prices been paid for the implants. Although it may be neither desirable nor possible to use the least expensive model and price in every hospital, the potential for cost reductions in the purchase of implants is substantial.

Guidelines for managing domestic abuse when male and female partners are patients of the same physician. The Delphi Panel and the Consulting Group.

OBJECTIVE: To provide clinical guidelines for primary care physicians who are dealing with domestic abuse and who have both the abused woman and her partner as patients. PARTICIPANTS: A 15-member expert panel with members having experience in family practice, gynecology, emergency medicine, medical ethics, nursing, psychology, law, and social work; an 11-member consulting group with members representing medicine, consumers, police, psychology, social work, and nursing; and participants from focus groups including 48 previously abused women and 10 previously abusive men. Members of the expert panel and the consulting group were recruited by the research team. Focus group members were recruited through the agencies from which they were receiving services. EVIDENCE: Available research information, and opinions of the expert panel, the consulting group, and the focus group participants. CONSENSUS PROCESS: Scoring of 144 clinical scenarios was performed by the expert panel using a modified Delphi technique involving 4 iterations. Scenarios were rated in terms of best practice for primary care physicians dealing with suspected and confirmed cases of physical abuse. Consulting group members and focus group participants then commented on the panel's results. Final guidelines were approved by the panel and the consulting group, with comments reserved in the guidelines for information from focus group participants. CONCLUSIONS: It is not a conflict of interest for the physician to deal with abuse of the female partner when both partners are patients. Both patients have a right to autonomy, confidentiality, honesty, and quality care. Patients should be dealt with independently, thereby facilitating assessment of the magnitude and severity of the victim's injuries. Physicians should not discuss the possibility of domestic abuse with the male partner without the prior consent of the abused female partner. Joint counseling is generally inadvisable and should be attempted only when the violence has ended, provided both partners give independent consent and the physician has adequate training and skills to deal with the situation without escalating the violence. If the physician feels unable to deal effectively with either patient because of the dual relationship, referral to another qualified physician is preferred.

Economic analysis of respiratory rehabilitation.

STUDY OBJECTIVE: We report on the incremental costs associated with improvements in health-related quality of life (HRQL) following 6 months of respiratory rehabilitation compared with conventional community care. DESIGN: Prospective randomized controlled trial of rehabilitation. SETTING: A respiratory rehabilitation unit. PARTICIPANTS: Eighty-four subjects who completed the rehabilitation trial. INTERVENTION: Two months of inpatient rehabilitation followed by 4 months of outpatient supervision. MEASUREMENTS AND RESULTS: All costs (hospitalization, medical care, medications, home care, assistive devices, transportation) were included. Simultaneous allocation was used to determine capital and direct and indirect hospitalization costs. The incremental cost of achieving improvements beyond the minimal clinically important difference in dyspnea, emotional function, and mastery was $11,597 (Canadian). More than 90% of this cost was attributable to the inpatient phase of the program. Of the nonphysician health-care professionals, nursing was identified as the largest cost center, followed by physical therapy and occupational therapy. The number of subjects needed to be treated (NNT) to improve one subject was 4.1 for dyspnea, 4.4 for fatigue, 3.3 for emotion, and 2.5 for mastery. CONCLUSION: Cost estimates of various approaches to rehabilitation should be combined with valid, reliable, and responsive measures of outcome to enable cost-effectiveness measures to be reported. Comparison studies with the same method are necessary to determine whether the improvements in HRQL that follow inpatient rehabilitation are cheap or expensive. Such information will be important in identifying the extent to which alternative approaches to rehabilitation can influence resource allocation. A consideration of cost-effectiveness from the perspective of NNT may be useful in the evaluation of health-care programs.

Home mechanical ventilation. Demographics and user perspectives.

Although the number of users of home mechanical ventilation (HMV) is increasing, information regarding the users' perceptions of the impact of HMV on their lives is incomplete. We administered an open-ended questionnaire to 98 (48 male, 50 female) HMV users aged (mean +/- SD) 47.4 +/- 19.5 years with COPD (9%), thoracic restrictive disease (43%), and neuromuscular disease (48%). At the time of survey, subjects had received HMV for 59.5 +/- 58.3 months. Fifty-three percent were ventilated electively. Ventilator use was continuous (18%), at night only (37%), or at night with occasional daytime use (45%). Twenty-seven (28%) individuals identified themselves as being totally independent while 32 (33%) rated themselves as partially dependent on caregiver assistance for daily activities. Only 37 (38%) considered that they had made an informed choice when first starting HMV whereas 54 (55%) did not. The impact of using a mechanical ventilator was believed to be overwhelmingly positive (87%). Positive comments regarding the impact of the ventilator on lifestyle were grouped in the following categories: life sustaining, facilitating mobility, and improving physical symptoms. Negative comments were grouped in the following categories: limiting mobility, equipment issues, and social implications. HMV users with a tracheostomy volunteered significantly fewer positive statements than those ventilated noninvasively (p < 0.05). Whereas 52 (53%) of users indicated that they had experienced initial difficulties in coping with the ventilator, only 11 (11%) identified difficulties at the time of the survey.

Randomised controlled trial of respiratory rehabilitation.

Disability associated with chronic obstructive pulmonary disease has led to the development of rehabilitation programmes that aim to increase exercise tolerance and improve quality of life. Many reports of the benefits of rehabilitation have been from uncontrolled trials and unsupervised programmes. In view of the commitment asked of patients, their families, and health-care professionals, rehabilitation should be justified by a demonstration of sustained improvement over conventional treatment. We undertook a prospective randomised controlled trial of respiratory rehabilitation in 89 subjects (44 men, 45 women) aged 66 (SD 7) years with severe but stable chronic obstructive pulmonary disease who received rehabilitation or conventional community care. The treatment group were rehabilitated as inpatients for 8 weeks and supervised as outpatients for 16 weeks. Primary outcome measures of exercise tolerance and quality of life were made at baseline and repeated at 12, 18, and 24 weeks. The difference between baseline and last follow-up was significant for 6 min walk distance (37.9 m [95% CI 10.8-65.0], p = 0.0067) and submaximal cycle time (4.7 min [2.1-7.3]). There were also significant differences in questionnaire assessment of dyspnoea (p = 0.0061), emotional function (p = 0.0150), mastery (p = 0.0002), and dyspnoea index (p = 0.0053). Improvements in exercise tolerance and quality of life can be achieved and sustained for 6 months in patients undergoing respiratory rehabilitation compared with those receiving conventional care.

Naturopathy in Canada: changing relationships to medicine, chiropractic and the state.

It is said that we can learn as much about social processes from so-called 'deviant' institutions than from the more legitimate. 'Deviant' medical occupations have not attracted much attention from social scientists. Naturopathy is one of these nonconventional health occupations. It emerged in the 18th and 19th centuries and moved to Canada from the United States and Europe early in the 20th. The social history of naturopathy in Canada illustrates the importance of processes of occupational formation and organization as well as state recognition or legitimation. Furthermore, the development of naturopathy shows the importance of state-occupation and naturopathy-chiropractic relationships as well as the often noted relationships with the dominant health occupation of medicine. Incidentally noted are the changing relationships with the state and the dominance of the ideology of science.